Tumor necrosis factor-α (TNF-α) is produced by macrophages activated in a host immune response for bacterial infection and tumor diseases, and various several cells. This cytokine has been known as an important medium in the inflammatory response, and is an inflammatory cytokine that plays a key role in inflammatory diseases, such as rheumatoid arthritis (RA), psoriatic arthritis, Crohn's disease, psoriasis, and ankylosing spondylitis (AS). For example, TNF-α keeps synovial inflammation and continuously destroys bones and cartilages in rheumatic arthritis. Therefore, the inhibition of the specific biological activity of TNF-α is required, and thus various biological preparations for inhibiting TNF-α have been developed for the purpose of preventing the cellular response mediated by TNF-α and adjusting activities of proinflammatory cytokines and the procedures regulated by TNF-α.
Meanwhile, the bone is one of the important parts of the human body that structurally support muscles or organs and store calcium or other essential minerals, in other words, materials, such as phosphorus and magnesium in the body. Therefore, adult bones after the completion of growth maintain balance thereof until death without stopping while the generation and absorption procedures of removing old bones and substituting for new bones are repeated very dynamically and continuously.
It has been known that two kinds of cells are greatly involved in bone remodeling. One of the two kinds of cells corresponds to osteoblasts, which generate bones, and the other corresponds to osteoclasts, which destroy bones. The osteoblasts generate a receptor activator of nuclear factor-KB ligand (RANKL) and a decoy receptor thereof, that is, osteoprotegerin (OPG). When RANKL binds to RANK, which is a receptor on a surface of osteoclast progenitor cells, the osteoclast progenitor cells mature into osteoclasts, resulting in bone resorption. However, the binding of OPG to RANKL cuts off the binding between RANKL and RANK, thereby suppressing the formation of osteoclasts, thus preventing unnecessary bone resorption (Theill L E. et al., Annu Rev Immunol., 20:795-823 (2002); Wagner E F. et al., Curr Opin Genet Dev., 11:527-532 (2001)). The resorption or destruction of old bones is made by osteoclasts generated in blood cells (hematopoietic stem cells), and the osteoclasts make holes in bones to release a small amount of calcium into the blood, and the calcium is used to maintain the body functions (William J. et al., Nature., 423:337342 (2003)). Meanwhile, osteoblasts generated from bone cells fill the holes with collagen and cover the holes with hydroxyapatite of calcium and phosphorus, thereby making new rigid bones to reconstruct skeletons (Stains J P. et al., Birth Defects Res C Embryo Today., 75(1):72-80 (2005)). It takes about 100 days to disrupt old bones and rebuild new bones (Schwarz E M. et al., Curr Opin Orthop., 11:329-335 (2000)). While 100% of calcium content in bone is changed within 1 year in an infant, about 10-30% of the skeleton is rebuilt by the bone remodeling in an adult every year. Only if the bone destroying rate and the bone forming rate are equal, the bone density can be maintained as before. The imbalance in important bones may cause many diseases, and particularly, the diseases associated with bone damage due to osteoporosis and bone metastasis of cancer cells are representative.
Osteoporosis is a disorder in which bone mass decreases by various causes and the risk of bone fracture continuously increases due to the degeneration of microstructure in bone tissue. Osteoporosis is a condition in which the contents of minerals (e.g., calcium) and substrates of bone have been reduced, and osteoporosis occurs when the bone destroying action becomes superior to the bone forming action due to the imbalance of bone remodeling (Iqbal M M., South Med J., 93(1):2-18 (2000)). While the inner structure of normal bones has a compact structure, such as a mesh, the osteoporosis bone shows a widened space between structures and a thinner micro-architecture that becomes susceptible to skeletal fractures by even the slight impact. Osteoporosis diseases are classified into postmenopausal osteoporosis, in which the bone loss (2-3% a year) promptly appears upon initiation of menopause and the risk of spine compression and wrist bone fracture is increased; senile osteoporosis, in which it is developed slowly (0.5-1% a year) in elder men and women aged more than 70 years and induces gradual bone loss of hip and spine bones; and secondary osteoporosis, which is developed by diseases (endocrine diseases, gastrointestinal diseases, and malignant tumors), drugs (adrenal cortical hormones, anticancer chemotherapy, thyroid hormones, anticonvulsants, antiplatelets, methotexate, cyclosporine and GnRH), alcohol, smoking or accident, regardless of age (Rosen C J., N Engl J Med., 353(6):595-603 (2005); Davidson M., Clinicain Reviews., 12(4):75-82 (2002)).
Breast cancer, prostate cancer, or multiple myeloma are usually accompanied with bone metastasis (Kozlow W. et al., J Mammary Gland Biol Neoplasia., 10(2):169-180 (2005)), and the lifespan of patients having such cancers has been known to be dependent on bone metastasis. The reason why the mortality of patients having breast or prostate cancer is increased is that cancer cells are selectively metastasized into bones. The bone metastasis observed in breast cancer is almost an osteolytic metastasis leading to bone destruction, and the osteolytic metastasis has been known to be caused by the stimulation of osteoclasts rather than the direct influence of breast cancer cells on bones (Boyde A. et al., Scan Electron Microsc., 4:1537-1554 (1986)). Whereas, the bone metastasis found in prostate cancer is an osteoblastic metastasis. The osteoblastic metastasis has also been known to be closely associated with osteolysis. The cancer cells entering bones proliferate in bone-surrounding microenvironments to stimulate the activity of osteoclasts or osteoblasts, thereby determining whether the subsequent bone metastasis is osteolytic or osteoblastic (Choong P F. et al., Clin Orthop Relat Res., 415S:S19-S31 (2003)). The bone metastasis of cancer cells occurs in about 80% of breast cancer patients, and the metastasized breast cancer cells activate osteoclasts (Bendre M., et al., Clin Orthop Relat Res., 415(Suppl):S39-S45 (2003); Palmqvist P. et al., J Immunol., 169(6):3353-3362 (2002)). The activated osteoclasts destroy the balance of the bone-surrounding microenvironments to cause osteolysis, resulting in frequent pathological fractures, and also causing bone-related diseases, such as leukoerythroblastic anaemia, bone deformity, hypercalcemia, pain, and nervecompression syndromes (Roodman G D., N Engl J Med., 350:1655-1664 (2004)).
According to the health insurance medical expense payment materials analyzed by Health Insurance Policy Institute of Korean National Health Insurance Corporation from 2001 to 2008, the number of patients of “hair loss diseases” is estimated at 103,000 people in 2001, at 142,000 people in 2005 and at 165,000 people in 2008. It has increased by 60% in recently seven years. The number of patients in their 20 s to 40 s is estimated at 114,000 people and it is accounted for 69.5% of whole patients. In addition, the number of patients in their 10 s is estimated at more than 22,000 people. The number of male patients is estimated at 84,000, and at 80,000 female patients, which is slightly more than that of male. The number of patients of “hair loss” disease in 2008 Korean Health Insurance treatment are alopecia areata (130,000 people), cicatricial alopecia (20,000 people), androgenetic alopecia (9,000 people) and other nonscarring hair loss (8,000 people) in order.
Abroad, according to data in June 2003 International Hair and Beauty Studies, there are 250 million hair loss patients, and the prevalence rate of hair loss patients between the ages of twenty-four and fifty years old is 30-65%. In China, the number of hair loss patients is 300 million people in 2008. 30% of males in their 30 s and 50% of males in their 50 s show signs of hair loss, and the number of hair loss patients increases by 10-15% every year. In Japan, prevalence rate of hair loss is 26.5%, and the number of hair loss patients is estimated at 12.93 million people.
Currently, the preparations for treating hair loss are largely classified into pharmaceutical medicines, quasi-drugs, and cosmetics. The accessible prescription drug given by doctors is “Propecia”, which was developed and marketed by Merck (U.S.), and its active ingredient Finasteride has been approved as a drug for treating hair loss from the U.S. FDA in December 1997. Finasteride inhibits 5-α-reductase which converts testosterone to dihydrotestosterone (DHT), whereby it results in growth of thick and long hair. Although it has an effect for alleviating hair loss in the short term, side effects such as impotence, sexual dysfunction, and male breast enlargement have been reported. Minoxidil has been recognized in safety and efficacy as a drug available to purchase without a doctor's prescription, and it has been firstly approved as a spread drug for treating hair loss from the U.S. FDA in December 1997. It improves blood circulation and opens potassium channels to promote hair growth, but it has local responses, such as itching, rash, and frequent pulse.
Quasi-products for hair loss prevention and hair growth functions approved from Korea Food & Drug Administration include “Mobalryeok confidence” (CJ lion), “Hair Tonic” (Moracle), and “Moaenmoah” (LG Household & Health Care). As cosmetics, shampoos or products used in the scalp and hair have been sold to maintain or promote the health of skin and hair. The human hair cycle is largely divided into growth (anagen), cessation (catagen), and rest (telogen) stages. In the anagen stage, the activity of hair papillae is active, leading to active cell division, and thus the hair grows rapidly. The lifespan of hairs in the anagen stage ranges from 3 to 6 years, depending on the kind of hair. The hairs in the anagen stage accounts for 80-90% of the entire hair. When hair loss is in progress, shorter anagen and longer catagen lead to the reduction of the proportion of the hair in the anagen stage in the entire hair. In the catagen stage after the anagen stage, the generation of hairs becomes slower, and thus, the cell division and growth are ultimately stopped. The catagen stage continues for 1-1.5 months and occupies 1% of total hairs. In the telogen stage, which is the last stage of growth, hair follicles, and hair papillae are completely separated from each other, and the hair follicles are gradually contracted, and the hair roots are pushed upward, and finally the hair falls out. This stage lasts for about 3-4 month, and accounts for 4-14% of total hairs. When the activity of the hair papillae is again active after the telogen stage is ended, the hair papillae for new hair are generated, and the hair at the telogen stage is pushed upward, and completely removed from the scalp.
Throughout the entire specification, many papers and patent documents are referenced and their citations are represented. The disclosure of the cited papers and patent documents are entirely incorporated by reference into the present specification, and the level of the technical field within which the present invention falls, and the details of the present invention are explained more clearly.